PROJECT SUMMARY: At present, Alzheimer's Disease (AD) affects 5 million in the US alone, with numbers projected to double by 2050. AD is a progressive neurodegenerative disease, and there are no disease-modifying therapies. Biomarkers ? objective measures of physiological of pathophysiological states ? can accelerate therapeutic development by making clinical trials more targeted and more efficient. However, successful biomarker development requires availability of biosamples from well-characterized patient populations, attention to detail in sample collection and handling, and quality control (QC) for sources of preanalytical variability. The recently-renewed Penn ADCC follows a longstanding clinical cohort of cognitively normal subjects, subjects with mild cognitive impairment (MCI), patients with early AD, and patients with AD related diseases (ADRD), numbering 500 individuals total. We propose to form a stand-alone Biomarker Core (Core G) to augment efforts of the existing 6 Penn ADCC cores by creating a systematic resource for biofluid samples, an accompanying set of baseline biochemical data, and QC tools to enable biomarker discovery. To do this, we propose four specific aims. ? SPECIFIC AIM 1: Oversee and direct all banking and dispersal of biofluid samples from Clinical Core B. These biofluids will consist of CSF, plasma, and serum collected at each visit. ? SPECIFIC AIM 2: Characterize biochemical biomarkers previously reported in the literature to confirm diagnosis of AD, predict outcome in early (or prodromal) stages of AD, indicate target engagement with an experimental therapeutic, or monitor disease progression. Specific markers that will be assayed in all 500 ADCC Clinical Core subjects at baseline include CSF A?1-42, CSF t-tau, and CSF p-tau181, CSF neurofilament light chain (NF-L), CSF ferritin, plasma NF-L, plasma epidermal growth factor (EGF). Moreover, biochemical biomarkers emerging from early investigations in ADNI (such as CSF total and phospho-?-SYN, neurogranin, and Vilip1), may be incorporated if data from ADNI appears sufficiently promising. ? SPECIFIC AIM 3: Create and maintain reference pools of CSF, plasma, and serum samples from the ADCC Clinical Core cohort as well as cohorts of patients with ADRD from other Penn clinics, making them available to investigators within the ADCC, and throughout the wider AD research community. ? SPECIFIC AIM 4: Create biomarker readouts for quality of sample handling from protein profiles obtained from systematic sample perturbations. We will leverage separately-funded investigations in which replicate plasma aliquots are systematically perturbed (left at room temperature, subjected to freeze-thaw) prior to interrogation on an aptamer-based platform for >1000 protein analytes. Through these separately-funded investigations, we will be able to identify many protein candidates that change in a predictable way with these systematic perturbations. In this Aim, we will develop assays for these candidate proteins, creating ?readouts? for poor sample handling.